Cutaneous Perfusion Research Articles

Hyperspectral Imaging as an Early Biomarker for Radiation Exposure and Microcirculatory Damage.

Radiation exposure can lead to detrimental effects in skin microcirculation. The precise relationship between radiation dose received and its effect on cutaneous perfusion still remains controversial. Previously, we have shown that hyperspectral imaging (HSI) is able to demonstrate long-term reductions in cutaneous perfusion secondary to chronic microvascular injury. This study characterizes the changes in skin microcirculation in response to varying doses of ionizing radiation and investigates these microcirculatory changes as a possible early non-invasive biomarker that may correlate with the extent of long-term microvascular damage. Immunocompetent hairless mice (n = 66) were exposed to single fractions of superficial beta-irradiation in doses of 0, 5, 10, 20, 35, or 50 Gy. A HSI device was utilized to measure deoxygenated hemoglobin levels in irradiated and control areas. HSI measurements were performed at baseline before radiation exposure and for the first 3 days post-irradiation. Maximum macroscopic skin reactions were graded, and histological assessment of cutaneous microvascular densities at 4 weeks post-irradiation was performed in harvested tissue by CD31 immunohistochemistry. CD31 immunohistochemistry demonstrated a significant correlation (r = 0.90, p < 0.0001) between dose and vessel density reduction at 4 weeks. Using HSI analysis, early changes in deoxygenated hemoglobin levels were observed during the first 3 days post-irradiation in all groups. These deoxygenated hemoglobin changes varied proportionally with dose (r = 0.98, p < 0.0001) and skin reactions (r = 0.98, p < 0.0001). There was a highly significant correlation (r = 0.91, p < 0.0001) between these early changes in deoxygenated hemoglobin and late vascular injury severity assessed at the end of 4 weeks. Radiation dose is directly correlated with cutaneous microvascular injury severity at 4 weeks in our model. Early post-exposure measurement of cutaneous deoxygenated hemoglobin levels may be a useful biomarker for radiation dose reconstruction and predictor for chronic microvascular injury.

Significance of the follicular pathway for dermal substance penetration quantified by laser Doppler flowmetry

The understanding of transdermal substance penetration pathways remains an important field for the development of future topical drugs and cosmetics. Laser Doppler flowmetry is a well-established method for evaluating cutaneous perfusion. In a study on 6 healthy male volunteers, we topically applied the vasoactive substance benzyl nicotinate on two test areas with open and obturated hair follicles and measured changes in the blood flow by Doppler flowmetry. Contrary to occluded follicles, the application onto the test area with open follicles led to a statistically significant perfusion increase within the first 5 minutes, emphasizing the importance of the follicular pathway for epidermal penetration.

HOMA MODELING IS SIGNIFICANTLY ASSOCIATED TO THE CUTANEOUS BLOOD PERFUSION RESPONSES OF INSULIN

A deviation from normal in HOMA modeling of β-cell function and sensitivity (S) are associated with a state of insulin sensitivity or resistance. Iontophoretic delivery of insulin induces endothelial-mediated vasodilatation and an increase of blood perfusion of the cutaneous microcirculation. The relationship between HOMA models and the cutaneous perfusion responses to insulin is unclear. A prospective trial was performed in otherwise healthy, non-diabetic men (n=9) and women (n=2). HOMA%β and %S were calculated from fasting blood samples. Iontophoresis with insulin and placebo was performed in the lower leg. Laser Doppler flowmetry characterized peak blood perfusion unit (BPU) responses (%change from BL) to iontophoretic conditions. BPU response of the placebo was subtracted from that of insulin (NetIns). Descriptive statistics were performed to characterize the cohort for demographics, NetIns, HOMA%β and HOMA%S. Separate regression analyses determined the linearity between NetIns and HOMA%β and %S. The cohort was 40±12 years old, 1.73±0.10 meters tall, 79.6±14.4 kg, and a BMI of 25.9±3.5. HOMA%B was calculated to be 168.9±87.2 and %S 53.4±24.6. The NetIns response was 286±264% and had a significant negative association to HOMA%β (R2=0.51;p=0.01) and positive association to %S (R2=0.40;p=0.02). Our findings demonstrate that the cutaneous microvascular endothelium is adversely affected by changes to peripheral insulin sensitivity and β-cell function. The deviation from a state of insulin sensitivity to that of resistance may be ascertained by studying the cutaneous microvasculature using iontophoretic methodology.

Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P < 0.05). However, during both exercise bouts, there were no differences in CVC or sweating between the treatment sites (all P > 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise.

PO-0344 Development Of A Paediatric Model To Mimic Reduced Cutaneous Blood Flow: Validation Using Laser Doppler And Photoplethysmography

Background Skin blood flow is highly variable accounting for 5–33% of cardiac output (Kenny 2011), and is often one of the first organs to change during early shock. In children, capillary refill time (CRT) is a crucial component of cardiovascular assessment and, despite marked variability, it remains a useful predictor of significant illness in children (Tibby 1999, Craig 2010). To allow development of new technologies to assess cutaneous blood flow a simple but valid model of reduced perfusion is required. Aims 1) Develop an acceptable paediatric model for reduced cutaneous perfusion, 2) Assess the ability of laser Doppler (LD) and green light photoplethysmography (gPPG) to detect these changes. Participants and methods Healthy children (5–17 years) were recruited. Simultaneous forearm LD blood flow and gPPG CRT measurements were obtained at baseline (room temperature) and during localised cooling of the arm (4 o C microenvironment). gPPG CRT was measured using a reflectance mode gPPG coupled with an automated pressure application system. Results Ten children completed the study over a typical timeframe of 45 min. Median LD blood flow decreased significantly from baseline during the cold exposure (P Conclusion This model appears to be both feasible and acceptable to children. Confirmation of reduced blood flow is observed using LD. Our automated CRT utilising gPPG appears useful in this model. After additional validation, the suitability and usefulness of automated CRT could be assessed in paediatric clinical trials with a view to improving recognition of early shock.

The Noninvasive Carbon Dioxide Gradient (NICO2G) During Hemorrhagic Shock

Hemorrhagic shock (HS) is a setting in which both pulmonary and cutaneous perfusion may be impaired. The goals of this study were to evaluate the relationship between end-tidal (etCO2), transcutaneous (tPCO2), arterial carbon dioxide (PaCO2) and lactate during lethal HS and to assess the effect of progressive HS on those variables and on a new variable, the noninvasive CO2 gradient ([NICO2G] or the difference between tPCO2 and etCO2). Ten consciously sedated swine were hemorrhaged, by means of a computerized exponential protocol, of up to 80% estimated blood volume for 20 min. End-tidal carbon dioxide, tPCO2, PaCO2, and lactate measurements were taken at baseline and every 5 min thereafter, that is, after 25%, 44%, and 62% total blood volume hemorrhage (TBVH) and at cardiac arrest. Cardiac arrest occurred on average at 67% TBVH. Data were analyzed by linear regression and one-way repeated-measures analysis of variance and are presented as means ± SD. Forty-nine paired measurements were made. There was no overall relationship between NICO2 variables and PaCO2: PaCO2 vs. tPCO2 (r2 = 0.002, P = 0.78); PaCO2 vs. etCO2 (r2 = 0.0002, P = 0.93). Rather, NICO2G increased at each level of blood loss: 4.0 ± 24.9 at baseline, 6.3 ± 35.7 at 25% TBVH, 25.0 ± 37.6 at 44% TBVH, 55.0 ± 33.9 at 62% TBVH, and 70.0 ± 33.2 at cardiac arrest (P < 0.05). Similarly, tPCO2 increased and etCO2 decreased at each level. Linear regression of NICO2G and lactate showed a better correlation than was observed for the other two variables: NICO2G, r2 = 0.58; tPCO2, r2 = 0.46; etCO2, r2 = 0.26. During HS, NICO2 monitors lose accuracy for approximating the PaCO2 but gain usefulness as hemodynamic monitors. Also, by combining data from two different organ systems, NICO2G demonstrated improved correlation with lactate than did either etCO2 or tPCO2 alone.

OP0091 A Retrospective Look at the Recurrence of Digital Ulcers in Patients with Scleroderma after Discontinuation of Oral Treprostinil

BackgroundIschemic digital ulcers (DU) are a frequent complication in systemic sclerosis, estimated to occur in over 40% of patients. Treprostinil diethanolamine, a newer prostacyclin analog that has been developed for...

Adenosine receptor inhibition attenuates the suppression of postexercise cutaneous blood flow

The time-dependent contributions of active vasodilation (e.g. nitric oxide) and noradrenergic vasoconstriction to the postexercise suppression of cutaneous perfusion despite persistent hyperthermia remain unknown. Moreover, adenosine receptors have been shown to mediate the decrease in cutaneous perfusion following passive heating. We examined the time-dependent modulation of nitric oxide synthase, noradrenergic vasoconstriction and adenosine receptors on postexercise cutaneous perfusion. Eight males performed 15 min of high-intensity (85% VO2 max) cycling followed by 60 min of recovery in temperate ambient conditions (25°C). Four microdialysis probes were inserted into the forearm skin and continuously infused with: (1) lactated Ringer solution (Control); (2) 10 mm N(G)-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase inhibitor); (3) 10 mm bretylium tosylate (BT; inhibitor of noradrenergic vasoconstriction); or (4) 4 mm theophylline (THEO; adenosine receptor inhibitor). Cutaneous vascular conductance (CVC) was expressed as a percentage of maximum and was calculated as perfusion units (laser Doppler) divided by mean arterial pressure. End-exercise CVC was similar in Control, THEO and BT (P > 0.1), but CVC with l-NAME (39 ± 4%) was lower than Control (59 ± 4%, P < 0.01). At 20 min of recovery, Control CVC (22 ± 3%) returned to baseline levels (19 ± 2%, P = 0.11). Relative to Control, CVC was reduced by l-NAME for the first 10 min of recovery whereas CVC was increased with BT for the first 30 min of recovery (P < 0.03). In contrast, CVC with THEO was elevated throughout the 60 min recovery period (P ≤ 0.01) compared to Control. We show that adenosine receptors appear to have a major role in postexercise cutaneous perfusion whereas nitric oxide synthase and noradrenergic vasoconstriction are involved only earlier during recovery.

Influence of cutaneous and muscular circulation on spatially resolved versus standard Beer-Lambert near-infrared spectroscopy.

The potential interference of cutaneous circulation on muscle blood volume and oxygenation monitoring by near‐infrared spectroscopy (NIRS) remains an important limitation of this technique. Spatially resolved spectroscopy (SRS) was reported to minimize the contribution of superficial tissue layers in cerebral monitoring but this characteristic has never been documented in muscle tissue monitoring. This study aims to compare SRS with the standard Beer–Lambert (BL) technique in detecting blood volume changes selectively induced in muscle and skin. In 16 healthy subjects, the biceps brachii was investigated during isometric elbow flexion at 70% of the maximum voluntary contractions lasting 10 sec, performed before and after exposure of the upper arm to warm air flow. From probes applied over the muscle belly the following variables were recorded: total hemoglobin index (THI, SRS‐based), total hemoglobin concentration (tHb, BL‐based), tissue oxygenation index (TOI, SRS‐based), and skin blood flow (SBF), using laser Doppler flowmetry. Blood volume indices exhibited similar changes during muscle contraction but only tHb significantly increased during warming (+5.2 ± 0.7 μmol/L·cm, an effect comparable to the increase occurring in postcontraction hyperemia), accompanying a 10‐fold increase in SBF. Contraction‐induced changes in tHb and THI were not substantially affected by warming, although the tHb tracing was shifted upward by (5.2 ± 3.5 μmol/L·cm, P < 0.01). TOI was not affected by cutaneous warming. In conclusion, SRS appears to effectively reject interference by SBF in both muscle blood volume and oxygenation monitoring. Instead, BL‐based parameters should be interpreted with caution, whenever changes in cutaneous perfusion cannot be excluded.

Forearm–finger skin temperature gradient as an index of cutaneous perfusion during steady‐state exercise

The purpose of this study was to examine whether the forearm-finger skin temperature gradient (T(forearm-finger)), an index of vasomotor tone during resting conditions, can also be used during steady-state exercise. Twelve healthy men performed three cycling trials at an intensity of ~60% of their maximal oxygen uptake for 75 min separated by at least 48 h. During exercise, forearm skin blood flow (BFF ) was measured with a laser-Doppler flowmeter, and finger skin blood flow (PPG) was recorded from the left index fingertip using a pulse plethysmogram. T(forearm-finger) of the left arm was calculated from the values derived by two thermistors placed on the radial side of the forearm and on the tip of the middle finger. During exercise, PPG and BFF increased (P<0.001), and T(forearm-finger) decreased (P<0.001) from their resting values, indicating a peripheral vasodilatation. There was a significant correlation between T(forearm-finger) and both PPG (r = -0.68; P<0.001) and BFF (r = -0.50; P<0.001). It is concluded that T(forearm-finger) is a valid qualitative index of cutaneous vasomotor tone during steady-state exercise.

Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion

IntroductionTreprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.MethodsScleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.ResultsNineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.ConclusionsOral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma.Trial RegistrationClinicalTrials.gov NCT00848939.Electronic supplementary materialThe online version of this article (doi:10.1186/ar4216) contains supplementary material, which is available to authorized users.

Microcirculatory response to experimentally-induced whole body heat stress in healthy humans

Vasodilation and increased skin blood flow (also sweating) are influential in heat dissipation during heat exposure and exercise. It is unclear how heat stress influences microcirculation. Side dark-field imaging visualizes the blood flow at the capillary level and helps to assess perfusion heterogeneity. Clinical and experimental data show that the sublingual region is clinically relevant for detecting microcirculatory alterations and more represents central microcirculation than cutaneous perfusion. We hypothesize that whole body heat stress may increase capillary density.

Electrical stimulation to accelerate wound healing.

BackgroundThere are several applications of electrical stimulation described in medical literature to accelerate wound healing and improve cutaneous perfusion. This is a simple technique that could be incorporated as an adjunctive therapy in plastic surgery. The objective of this review was to evaluate the results of randomized clinical trials that use electrical stimulation for wound healing.MethodWe identified 21 randomized clinical trials that used electrical stimulation for wound healing. We did not include five studies with treatment groups with less than eight subjects.ResultsElectrical stimulation was associated with faster wound area reduction or a higher proportion of wounds that healed in 14 out of 16 wound randomized clinical trials. The type of electrical stimulation, waveform, and duration of therapy vary in the literature.ConclusionElectrical stimulation has been shown to accelerate wound healing and increase cutaneous perfusion in human studies. Electrical stimulation is an adjunctive therapy that is underutilized in plastic surgery and could improve flap and graft survival, accelerate postoperative recovery, and decrease necrosis following foot reconstruction.

Vascular Dysfunction in Sleep Apnea

See related article, pp 417–424 Cardiovascular disease remains one of the leading causes of morbidity and mortality. Obstructive sleep apnea (OSA) has been increasingly implicated in a breadth of cardiovascular diseases, including systemic hypertension, heart failure, stroke, arrhythmias, myocardial ischemia, and pulmonary arterial hypertension.1 The importance of this association, especially in the context of OSA as an etiologic factor, is compellingly relevant to disease management strategies, given the high prevalence of OSA and its likely rising trajectory secondary to the ongoing obesity epidemic.2 OSA may be present in approximately 20% of American adults, only a minority of whom have ever been diagnosed; this is true even for patients with established cardiovascular disease3 and despite the widespread availability of several effective treatment modalities (including continuous positive airway pressure [CPAP]). It is only over the past 2 decades that serious investigative interest has been paid to the interactions between OSA and cardiac and vascular disease and dysfunction. Deciphering the mechanisms, causal relationships, and potential therapeutic targets in the links between OSA and cardiovascular morbidity has not been an easy task, in part because of the constellation of comorbidities that characterize a large proportion of sleep apnea patients. OSA leads to multiple sources of cardiovascular stress, including nocturnal hypoxemia and hypercapnia, precipitous intrathoracic pressure changes, repetitive arousals, and poor sleep quality with consequent sleep deprivation. These, in turn, have been linked to endothelial dysfunction,4 systemic inflammation, sympathetic activation,5 metabolic dysregulation, hypercoagulability, and atrial enlargement, the combination of which may contribute to the initiation and progression of a range of cardiovascular diseases. Of these, endothelial dysfunction …

Myocardial Perfusion by Myocardial Contrast Echocardiography and Endothelial Dysfunction in Obstructive Sleep Apnea

Obstructive sleep apnea is associated with increased cardiovascular morbidity and mortality. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial dysfunction in normotensive subjects with moderate-to-severe obstructive sleep apnea, who were compared with hypertensive and healthy subjects, as well as the impact of continuous positive airway pressure treatment on obstructive sleep apnea subjects. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), cutaneous perfusion responses to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, and circulating endothelial and endothelial progenitor cells in a total of 108 subjects (n=36 each of matched obstructive sleep apnea, hypertension, and healthy cohorts). Subjects with obstructive sleep apnea and hypertension demonstrated abnormal myocardial perfusion (P<0.001 for both comparisons), attenuated brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) compared with healthy individuals. Both hypertensive and obstructive sleep apnea patients showed significant improvements in myocardial perfusion (P<0.01), brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) after 26 weeks of continuous positive airway pressure therapy. There were no significant differences in pulse wave velocity and endothelial cells across the 3 groups. Concomitant endothelial dysfunction and impaired myocardial perfusion are present in otherwise normal subjects with moderate-to-severe obstructive sleep apnea, and effective continuous positive airway pressure treatment reverses many of these macrovascular/microvascular abnormalities.

Comparison of infrared thermography and laser speckle contrast imaging for the dynamic assessment of digital microvascular function

ObjectivesLaser speckle contrast imaging (LSCI) is a novel non-invasive microvascular imaging modality. The present study evaluates the validity and reliability of LSCI by comparison with infrared thermography (IRT) for the dynamic assessment of digital microvascular function in healthy volunteers. MethodsSubjects attended on 3 occasions. Simultaneous assessment of cutaneous perfusion at 3 distinct regions of interest (ROI) within the hands was undertaken using LSCI and infrared thermography (IRT) at baseline, and at 13s intervals over 15min following a standardised local cold challenge. Endpoints for evaluation included absolute measurements at baseline and following cold stress, in addition to the characteristics of the re-warming curves (maximum % recovery and maximum gradient). Visits 1 and 2 were undertaken in identical conditions (ambient temperature 23°C) to assess reproducibility, whereas visit 3 was undertaken at a lower ambient room temperature of 18°C to evaluate responsiveness to reduction in ambient room temperature. ResultsFourteen healthy participants completed the study. There was greater variability in the data generated using LSCI compared with the highly damped IRT, reflecting greater sensitivity of LSCI to physiological variation and movement artefact. LSCI and IRT correlated well at baseline and following cold challenge for all endpoints (rs for pooled data between 0.5 and 0.65, p<0.00005). Reproducibility of both IRT and LSCI was excellent (ICCs>0.75) for absolute assessments but lower for re-warming curve characteristics. LSCI provides greater spatial resolution than IRT identifying variation in cutaneous perfusion within the hands most likely associated with the presence of arteriovenous anastamoses. Both techniques were responsive to reduction in ambient room temperature. Effect sizes were greatest for IRT than LSCI (e.g. −1.17 vs. −0.85 at ROI 1 at baseline) although this may represent heat transfer rather than altered vascular perfusion. DiscussionIn the dynamic assessment of digital vascular perfusion, LSCI correlates well with IRT, is reproducible and responsive to reduction in ambient room temperature. Absolute measurements appear preferable to parameters derived from re-warming curve characteristics when assessing digital perfusion following cold challenge. The greater temporal and spatial resolution of LSCI compared with IRT may facilitate the development of novel assessment tools of autonomic function and digital cutaneous perfusion.

Cutaneous blood flow and peripheral resistance in type II diabetes as compared to intermittent claudication patients

Insulin deficient, type I diabetic patients have reduced skin blood flow reserve. It is not known whether these skin perfusion abnormalities also exist in non-insulin dependent (type II) diabetic patients. An additional open question is whether the reduced skin blood flow is due to increased resistance of the cutaneous microvasculature or to decreased peripheral perfusion pressure due to increased atherosclerosis in the diabetic population. We measured skin blood flow by laser Doppler flowmetry in patients with type II non-insulin treated diabetes. Limb systolic blood pressure was measured distally using a sensitive sonar Doppler device at the finger and toe. The ratio of pressure to flow was computed as an index of peripheral blood flow resistance. To assess the effect of cutaneous blood flow resistance, we elicited maximal vasodilation by increasing local skin temperature directly at the site of the laser Doppler probe. We compared blood flow and pressure in diabetic patients with the values in non-diabetic control patients. As a further control population, we also assessed these same parameters in non-diabetic patients with peripheral vascular disease, which may be expected to decrease large arterial blood flow pressure without directly affecting the microvasculature. There were 68 type II diabetic patients, 18 non-diabetic control subjects, and 25 non-diabetic patients with intermittent claudication. We measured skin blood flow at the dorsal surfaces of the finger and toe, sites with primarily nutritive capillary perfusion, and at the plantar surfaces of the finger and toe, where arteriovenous shunt perfusion predominates. Heat stimulated flow was markedly lower for the diabetic patients at the finger dorsal surface (16.5 ± 1.4 ml/min/100 g vs 29.8 ± 4.4 ml/min/100 g in the non-diabetic group (p < 0.05). The resistance index was 13.2 ± 1.9 in the diabetic patients and 6.8 ± 1.7 in the controls (p < 0.05). At the toe dorsum, basal temperature flow was significantly lower in the diabetic group (0.6 ± 0.1 ml/min/100 g) than in the non diabetic group (1.1 ± 0.2 ml/min/100 gm) with resistance index almost twice as high (379 ± 32) in the diabetic group versus non-diabetic controls (208 ± 36) [p < 0.01 for both comparisons]. With the local application of heat, there was a much larger increase in flow in the non-diabetic subjects than in the diabetic group. The resistance index dropped much more with heat stimulation for the non-diabetic patients (10.8 ± 3.3) than for the diabetic patients (50.6 ± 10.4) [p < 0.01] There was a lesser rise in flow at the toe pulp surface with heat in the diabetic patients (31.3 ± 3.0 ml/min/199 gm) than in the control subjects (45.4 ± 5.9 ml/min/100 gm; p < 0.05) with a higher resistance index (13 ± 4) than in the non-diabetic subjects (4 ± 1) [p < 0.05]. The claudication patients had substantially greater flow at the toe dorsal surface at basal temperature (2.2 ± 0.4 ml/min/100 gm) with significantly lower resistance index (126 ± 24) than the non-diabetic controls (p < 0.05). At 44°C, toe dorsum flow was significantly higher (17.8 ± 3.7 ml/min/100 gm) than in the diabetic patients with lower resistance index (17.0 ± 6.6) [p < 0.05]. Toe pulp flow at basal temperature was significantly higher (10.1 ± 2.0 ml/min/100 gm) than in either the diabetic (3.8 ± 0.6) or non-diabetic control groups (3.5 ± 1.4) [p < 0.05]. Skin blood flow is impaired in diabetes. The reduction is due to increased resistance in the capillary bed rather than to reduced perfusion pressure. The increased resistance was found only in the diabetic patients, not in the non-diabetic patients with peripheral vascular disease. To the contrary, there appeared to be a compensatory decrease in skin flow resistance in the patients with peripheral vascular disease. Thus, there is a small vessel disease which impairs cutaneous perfusion in diabetes, but there is no such effect on skin blood flow in non-diabetic patients with large vessel disease.

Deterministic nonlinear features of cutaneous perfusion are lost in diabetic subjects with neuropathy

The aim of this study was to analyze and compare the deterministic nonlinear structure of cutaneous laser Doppler flowmetry signals obtained from the forearm and foot of normal subjects and diabetic patients without neuropathy (D), with peripheral neuropathy (DPN) and with combined autonomic and peripheral neuropathy (DAN). Flow oscillations were evaluated under baseline conditions, after local warming of the skin to 44 °C and after warming plus iontophoresis of phenylephrine. The presence of nonlinearity was investigated by three complementary approaches: (i) attractor reconstruction, (ii) calculation of largest Lyapunov exponents (LLEs), and (iii) correlation dimension analysis. Conclusions were validated against surrogate stochastic time series generated by randomizing the Fourier phase of the raw data. In the control and D groups, the combination of phenylephrine and warming unmasked flowmotion with a prominent component at 0.1 Hz. Attractor reconstruction revealed toroidal structure and estimated LLEs were positive. LLEs decreased to zero and dimension estimates increased for surrogate data, consistent with loss of determinism. In diabetic subjects with neuropathy estimates of LLE were not significantly different from zero and dimensions were unaffected by phase randomization. Evidence for nonlinear structure was also obtained under baseline conditions in normal and D subjects, but was lost on warming alone. We conclude that deterministic control mechanisms contribute to cutaneous flowmotion, particularly when pseudo-quasiperiodic behavior is enhanced by phenylephrine. Nonlinear analysis of laser Doppler signals may provide previously unrecognized insights into the effects of diabetic neuropathy on perfusion because it can identify loss of complexity independently of the amplitude of the signals recorded.

Does detraining restore influence of exercise training on microvascular responses in streptozotocin-induced diabetic rats?

Several findings demonstrated that exercise training has therapeutic and protective effects in type 1 diabetes and could correct micro and macro vascular dysfunction. Regarding all benefits of exercise training on vascular function, however, the mechanisms and persistence of these benefits are only partially understood. Method: Male Wistar rats (220 ± 10 g, N = 85) were made diabetic by streptozotocin (60 mg/kg, subcutaneously). One week after diabetes induction, animals were submitted to exercise training for 10 weeks on a treadmill and detrained for 5 weeks. To characterize cutaneous microvascular responses by Laser Doppler flowmetery, animals were deeply anaesthetized by intra peritoneal injection of pentobarbital sodium and placed on a heating pad, a rectal thermometer was inserted, and body temperature was maintained at 37 ± 0.5 °C. A tracheotomy was performed to minimize respiratory difficulties. Results in diabetic rats after training: (1) l-arginine ( l-ARG) and Acetylcholine (Ach)-induced cutaneous perfusion were increased. However, these effects were reversed by detraining and Nw-nitro- l-arginine ( l-NNA); (2) sodium nitroprusside (SNP)-induced cutaneous perfusion did not significantly change; and (3) cutaneous microvascular responses to SNP were reduced after detraining. The results suggest that in diabetic rats, beneficial effect of regular exercise on cutaneous microvascular endothelium-dependent dilatation and l-ARG/Nitric oxide pathway activity was approximately reversed by 5 weeks of detraining. Training did not affect endothelium-independent dilatation; however, detraining reduced it significantly.

The Influence of Oral Magnesium Sulfate on Skin Microvasculature Blood Flow in Diabetic Rats

Microvascular disease is a major feature of type1 diabetes and results from long-standing structural and functional changes especially in the skin microvasculature. Magnesium (Mg) deficiency has recently been proposed as a novel factor implicated in the pathogenesis of diabetes complications such as vascular disturbance, but its mechanism of action is not completely elucidated. The present study was designed to determine whether chronic magnesium sulfate administration could control streptozocin-induced diabetes and improve endothelium-dependent and endothelium-independent dilatation, and identify its probable mechanism in the skin microvasculature of diabetic rats. Fifty male Wistar rats (220 ± 10 g) were divided into two diabetic and one control groups. One subgroup of diabetic received magnesium sulfate (10 g/l) in their drinking water, while two other groups had only tap water. Laser Doppler flow meter with iontophoresis was used to measure the relative changes in skin blood flow. We used acetylcholine (Ach), sodium nitroprusside (SNP), and N (w)-nitro-L-arginine (LNNA; NO synthase inhibitor) with magnesium sulfate (0.1 M) in control and experimental animal by microsyringe pump microinjection. SNP- and Ach-induced cutaneous perfusion increased significantly by Mg treatment in the diabetic groups, and local microinjection of magnesium sulfate (0.1 M) increased cutaneous blood flow in all groups (p < 0.01). However, the administration of LNNA prior to magnesium sulfate attenuated (p < 0.05) but not abolished the increase in cutaneous blood flow in diabetic and normal rats. From the results of this study, it may be concluded that Mg could improve skin microvasculature of diabetic rats with potentiation of nitric oxide pathway.